1. Randomized, Double-Blind, Controlled Study of Glycerol Phenylbutyrate in Hepatic Encephalopathy HEPATOLOGY 2014;59:1073-1083 전임의 1 년차 신재령

2. Introduction Hepatic encephalopathy(HE)  Spectrum of neuropsychiatric abnormalities ranging from confusion to coma, typically reversible  Pathophysiology of HE is incompletely understood  Elevated blood ammonia has long been suspected as important Current treatments, including poorly absorbed disaccharides (e.g.,lactulose) and antibiotics (e.g., rifaximin)  Reducing ammonia production and/or absorption in the intestine, but are not ammonia selective

3. Glycerol phenylbutyrate Three molecules of phenylbutyric acid (PBA) joined to glycerol by ester linkage acts by providing an alternate pathway for ammonia removal and waste nitrogen excretion in the form of urinary phenylacetyl glutamine (PAGN)

4. Patients and Methods Patients were randomly assigned in a blinded fashion in a 1:1 ratio  using a computerized central randomization schedule to receive 6 mL of GPB or matching placebo, orally, twice-daily, for 16 weeks Patients continued to receive their standard of care treatment, including lactulose, rifaximin, or both, until an on-study HE event

5. Patients and Methods Eligible patients included adults with cirrhosis who had experienced at least two episodes of HE or West Haven (WH) grade 2 or greater, in the previous 6 months, one of which was within 3 months of randomization

6. Patients and Methods Exclusion criteria  Use of putative ammonia-lowering agents (e.g., Lornithine-L-aspartate or sodium benzoate)  Hypersensitivity to GPB or its metabolites  Recreational drug use or alcohol consumption  Active complications of cirrhosis (e.g., sepsis or bleeding)  TIPS placement or revision within 90 days  Expected liver transplantation (LT) within 6 months  MELD score >25, serum creatinine >2 mg/dL, serum sodium <125 mEq/L, platelet count <35,000/lL, hemoglobin <8 g/dL, hematocrit <25%

7. Patients and Methods Safety assessments included vital signs, electrocardiograms (ECGs), and hematologic and chemistry evaluations Patients underwent a daily assessment by their designated caregiver based on the Clinical Hepatic Encephalopathy Staging Scale (CHESS)  Score of 3 generally corresponds to WH 2, For patients with a score 3, the caregiver was instructed to contact the study site

8. primary endpoint for the intention-to-treat (ITT) population was the proportion (expressed as %) of patients experiencing an HE event  defined as either WH grade  2 or an increase 1 in both the WH and asterixis grades, if baseline WH was 0 Prespecified secondary endpoints included time to first HE events and total HE events

9. Results

19. Conclusion Glycerol Phenylbutyrate reduced hepatic encephalopathy events as well as ammonia in patients with cirrhosis and Hepathic encephalopathy and its safety profile was similar to placebo The results further suggest that elevated blood ammonia plays an important role in the pathogenesis of recurrent overt Hepatic encephalopathy